The treatment of lung cancer has entered a new era with the identification of new molecular targets and the development of individualized treatment options. For patients with specific molecular abnormalities, targeted therapies result in robust improvements in tumor response and disease control duration. However, resistance to therapy occurs and a cure remains elusive. New approaches are needed to improve outcomes for these patients. In order to accomplish this, we need to identify novel methods to monitor patients for development of resistance with regards to specific targeted therapies. Another area of research involves developing new biomarkers to identify patients at risk for recurrence or sensitivity to specific therapeutic agents. New developments in the area of genomics, epigenetic and proteomics allow for application of these technologies in patients specimens from recent and new clinical trials conducted by the National Clinical Trials Network (NCTN). The ECOG-ACRIN group intends to establish a Translational Science Center that has a primary focus on thoracic malignancies to develop novel approaches to treat lung cancer and to develop new biomarkers that can subsequently be tested in prospective clinical trials. The main objectives of the Thoracic Malignancies Integrated Translational Science Center are: 1. To develop genomic, epigenomic and proteomics approaches to enhance biomarker discovery efforts in ongoing and planned ECOG-ACRIN studies; 2. To conduct pilot studies on existing lung cancer tumor specimens that will lead to prospective biomarker-based clinical trials; and 3. To rapidly translate the findings of the pilot projects and biomarker discovery efforts in clinical trials conducted by the ECOG-ACRIN Thoracic Committee. Salient among the proposed pilot projects include utilizing plasma DNA specimens to identify target cancer mutations, evaluation of new epigenetic markers to predict risk of recurrent disease in those with early stage lung cancer, studying the impact of LKB1 mutations in outcome for early stage lung cancer and testing novel methods to overcome resistance to targeted therapies. RELEVANCE: This proposal will study novel translational strategies to improve the outcomes for lung cancer. This center will focus on biomarker discovery; novel methods to detect dominant oncogenic mutations using peripheral blood, new strategies to overcome resistance to targeted therapies and will attempt to validate the findings in ongoing and planned ECOG-ACRIN clinical trials.